The development of coronary heart disease (CHD) is blunted by moderate levels of exercise training (EX). Mechanisms responsible for beneficial effects of EX are not known. The central theme of this Program Project Grant (PPG) is the hypothesis that EX is beneficial due to training- induced alterations in coronary vascular function. There are 3 major goals: A) elucidation of cellular molecular mechanisms for regulation of vascular smooth muscle (VSM) and endothelium in the coronary circulation, B) systematic determination of cellular/molecular mechanisms responsible for EX-induced changes in intrinsic vascular function, and C) application of this understanding of vascular cell biology and EX- induced coronary vascular adaptation to experimental models of CHD. The PPG formalizes and expands extensive collaborative efforts ongoing among this research team. An integrated experimental approach that examines coronary vascular function throughout the coronary tree of sedentary and EX pigs is presented. Projects 1 and 2 focus on VSM of conduit coronary arteries. Project 1 employs electrophysiology and imaging techniques to examine cellular/molecular mechanisms responsible for adaptations in sarcoplasmic reticulum Ca2+ release and Ca2+ extrusion in VSM. Project 2 will test the hypothesis that EX induces changes in VSM transmembrane signalling mechanisms and/or receptor/second messenger pathways. Projects 3 and 4 focus on the microcirculation . Project 3 examines control of vascular resistance and mechanisms responsible for EX-induced changes in myogenic reactivity and endothelium-mediated responses of coronary resistance arteries. Project 4 will determine mechanisms responsible for EX-induced changes in transvascular exchange using isolated microvessels and direct measures of permeability to different sized probes with and without vasodilators. Project 5 is designed to investigate the impact of EX-induced coronary vascular adaptations on a model of CHD. The focus is on the potential effects of EX on reactivity of vessels in collateral dependent myocardium and will determine whether EX blunts vascular dysfunction caused by chronic ischemia. Completion of the proposed research will dramatically improve understanding of: vascular cell biology, mechanisms of EX-induced coronary vascular adaptation, integration of blood flow control and vascular exchange, and interactions with CHD. This multi-level approach to the study of coronary vasomotor function after EX represents a new frontier in exercise physiology that holds the potential to transform concepts of EX- induced adaptation in the coronary circulation.